title: A smad signaling network regulates islet cell proliferation.
abstract: Pancreatic β-cell loss and dysfunction are critical components of all types of diabetes. Human and rodent β-cells are able to proliferate, and this proliferation is an important defense against the evolution and progression of diabetes. Transforming growth factor-β (TGF-β) signaling has been shown to affect β-cell development, proliferation, and function, but β-cell proliferation is thought to be the only source of new β-cells in the adult. Recently, β-cell dedifferentiation has been shown to be an important contributory mechanism to β-cell failure. In this study, we tie together these two pathways by showing that a network of intracellular TGF-β regulators, smads 7, 2, and 3, control β-cell proliferation after β-cell loss, and specifically, smad7 is necessary for that β-cell proliferation. Importantly, this smad7-mediated proliferation appears to entail passing through a transient, nonpathologic dedifferentiation of β-cells to a pancreatic polypeptide-fold hormone-positive state. TGF-β receptor II appears to be a receptor important for controlling the status of the smad network in β-cells. These studies should help our understanding of properly regulated β-cell replication.
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh, Pittsburgh, PA.
authors.forename: Yousef
authors.initials: Y
authors.lastname: El-Gohary
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Tulachan
authors.forename: John
authors.initials: J
authors.lastname: Wiersch
authors.forename: Ping
authors.initials: P
authors.lastname: Guo
authors.forename: Carey
authors.initials: C
authors.lastname: Welsh
authors.forename: Krishna
authors.initials: K
authors.lastname: Prasadan
authors.forename: Jose
authors.initials: J
authors.lastname: Paredes
authors.forename: Chiyo
authors.initials: C
authors.lastname: Shiota
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Xiao
authors.forename: Yoko
authors.initials: Y
authors.lastname: Wada
authors.forename: Marilyn
authors.initials: M
authors.lastname: Diaz
authors.forename: George
authors.initials: G
authors.lastname: Gittes
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000502:physiology*; D049109:Cell Proliferation; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta